Any scission into the body is detrimental and invariably results in cell loss. The need to keep cell loss to a minimum is particularly crucial during any surgical procedure performed on delicate and irreplaceable tissues, for example, ophthalmic or nerve tissue.
The cornea of the eye is comprised of five layers: epithelium, Bowman's membrane, stroma, Decemet's membrane, and endothelium. The endothelium layer is particularly vulnerable to trauma, and protection of the endothelium is particularly important because endothelial cells are infrequently, if ever, replaced as a normal process in adult life. The corneal endothelium is principally responsible for maintaining proper hydration of the stromal layer. The stromal layer has a tendency to imbibe fluid, a tendency which is counterbalanced by outward fluid transport via the endothelium. If the proper fluid balance is not maintained in the stromal layer, the cornea thickens and the characteristic transparency of the cornea is lost. Failure of the endothelium to perform its fluid transport function for even short periods of time will result in corneal thickening and visual clouding. In addition, cell loss or damage in the endothelial layer results in decreased vision. Because of the importance and vulnerability of the endothelial layer, it is necessary during eye surgery, such as cataract and retinal surgery or corneal transplants, to make provisions for the protection of the endothelial cells.
A significant factor causing cell loss during tissue scission is the traumatic change in environment experienced by the cells. Exposure to the atmosphere presents a far different environment for internal cells than is provided by the natural fluids in which they are bathed. To simulate the natural cellular environment during surgery thereby preventing cell damage, exposed tissue is frequently irrigated in solutions which attempt to approximate the chemical composition and/or physical properties of natural body fluids. The value of bathing ophthalmic tissue during surgery to prevent cell damage has long been recognized. For internal ocular tissues, such as the endothelium, the aqueous humor is the natural bathing fluid. Therefore, an ideal ophthalmic irrigating solution should simulate or surpass the cell preservation properties of the aqueous humor.
Of primary concern for any tissue irrigating solution is that the osmolality of the solution be generally isotonic relative to cellular fluids, so as to maintain equal osmotic pressure within and without the cell membranes. To this end, one of the early ophthalmic irrigating solutions was isotonic (0.9%) saline. However, it has long been recognized that isotonic saline is quite inadequate as an ophthalmic irrigating solution because its use has been shown to result in endothelial cell swelling, cell damage, and consequent corneal clouding.
Because of the inadequacy of isotonic saline, various alternative electrolyte solutions have been proposed as irrigating solutions, particularly ophthalmic irrigating solutions which more closely resemble the aqueous humor and prevent cell damage and corneal clouding. Standard electrolyte solutions primarily intended for intravenous injection, such as Ringer's solution and lactated Ringer's solution, have been used as ophthalmic irrigating solutions because they are readily available and are sterile.
An electrolyte solution specifically intended for ophthalmic irrigation is available from Alcon Laboratories, Inc. as BSS.RTM.. That solution, which may be characterized as being a balanced salt solution, contains the essential ions calcium, sodium, potassium, magnesium and chloride in generally optimal concentrations for ocular tissue, and has an acetate-citrate buffer system which is compatible with divalent calcium and magnesium ions.
Electrolyte solutions used for ophthalmic irrigation, such as lactated Ringer's solution and balanced salt solutions, represent improvements over normal saline because they provide necessary ions in addition to the sodium and chloride ions provided by isotonic saline. For example, magnesium is an important cofactor for adenosine triphosphotase, an enzyme which plays an important role in mediating the fluid transport pump in the eye. Calcium is necessary to maintain the endothelial junction, and potassium is an important factor in many biochemical processes. Moreover, the fluid transport pump of the endothelium requires a proper sodium, potassium ion ratio (Na+/K+) to function. Due to these additions the previously known electrolyte solutions used to irrigate ocular tissue have reduced, but not eliminated, corneal swelling and cell damage during surgery.
The need for improved ophthalmic irrigating solutions continues, particularly in view of new surgical techniques which may probe deeper into the eye requiring several hours of operating time. For example, surgical advances now permit surgery in the vitreous (posterior) chamber to remove opacified vitreous humor or to repair retinal detachment. Such operations can require up to three hours. Inner cells chances of damage increase the longer they are exposed, but improved irrigating solutions can help prevent damage resulting from exposure during lengthy procedures.
During eye surgery and particularly during surgery which requires extended periods of time, proper electrolytic balance alone is insufficient to protect the corneal endothelium. To prevent cell damage and maintain proper corneal thickness, an irrigating solution, in addition to maintaining electrolytic balance, must also provide metabolic support and must particularly provide factors needed for the enzyme-mediated sodium/potassium ion pump system through which excess fluid is removed from the stroma.
Factors determined to be necessary for sustained metabolism of endothelial cells include dextrose, glutathione and bicarbonate. All have been shown to be important in maintaining the structural integrity of endothelial cells. Dextrose provides a substrate for various metabolic pathways and glutathione has been shown to aid the adenosine-triphosphotase mediated metabolic pump by maintaining the proper sodium, potassium ion ratio. In addition, bicarbonate is useful in maintaining proper pH of the irrigating solution.
Glutathione bicarbonate-Ringer's solution (GBR) has incorporated the above-mentioned factors and is effective in maintaining corneal thickness and endothelial cell integrity for up to three hours. However, its use has been limited for reasons of sterility and stability.
U.S. Pat. Nos. 4,443,432 and 4,550,022 (Garabedian et al.) assigned to Alcon Laboratories, Inc. describe tissue irrigating compositions which comprise a balanced salt solution in combination with sodium bicarbonate, dextrose and glutathione. The entire contents of these two patents are hereby incorporated by reference in the present specification.
The role of gamma-aminobutyric acid (GABA) in stimulating the corneal endothelial fluid pump has been previously recognized. More particularly, prior studies have indicated that GABA enhances the pumping efficiency of the corneal endothelial fluid pump thereby promoting normal corneal function and preventing or minimizing corneal swelling. According to one study, the activity of GABA in this regard is comparable to or better than that of oxidized glutathione. See Dikstein et al., Experimental Eye Research, Vol. 31, pages 239-241 (1980).
A principal objective of the present invention is the provision of new compounds having GABA like activity and methods of synthesizing those compounds.
A further objective of the present invention is the provision of ophthalmic surgical irrigating solutions containing one or more compounds having GABA like activity and methods for their use.